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. 2006 Sep;50(9):3162–3165. doi: 10.1128/AAC.00269-06

Increase of the M Phenotype among Erythromycin-Resistant Streptococcus pneumoniae Isolates from Spain Related to the Serotype 14 Variant of the Spain9V-3 Clone

C Ardanuy 1,*, A Fenoll 2, S Berrón 2, L Calatayud 1, J Liñares 1; the Spanish Pneumococcal Infection Study Network†
PMCID: PMC1563508  PMID: 16940119

Abstract

Between 1998 and 2003 the rate of erythromycin resistance among pneumococci in Spain was 34.4%. Although the MLSB phenotype was prevalent (94.7%), the rate of the M phenotype increased from 3.3% to 8.9% (P < 0.01). Clonal dissemination of mef(E)-carrying strains of serotype 14 variant of the Spain9V-3 clone was the major contributor to this increase.

Increased resistance to macrolide in Streptococcus pneumoniae has been described worldwide (8-10, 14-16, 18-21, 23-27). In Europe, Mediterranean countries have the highest rates of erythromycin-resistant pneumococci, whereas northern European countries have the lowest (14-16, 20, 23, 29). In Spain, the rate of erythromycin resistance has increased progressively, from 4.3% in the period from 1979 to 1990 (19) to 22.5% in the period from 1990 to 1996 (14) and 34.5% in 2001 and 2002 (26).

Macrolide resistance in pneumococci is mainly mediated by two mechanisms: enzymatic target site modifications mediated by ErmB methylases that confer the MLSB phenotype and active drug efflux pumps encoded by mef genes that confer the M phenotype. Other less frequent mechanisms have also been described: point mutations in ribosomal proteins L4 and L22 or in 23S rRNA (17, 28). The MLSB phenotype is prevalent in Spain and in most European countries, whereas the M phenotype predominates in North America, England, and Greece (1, 8, 15, 21, 29).

In this paper, macrolide-resistant pneumococci with the M phenotype from Spain were investigated.

Evolution of macrolide resistance in pneumococci.

Among 15,084 pneumococci recorded at the Spanish Reference Laboratory (1998 to 2003), 5,194 (34.4%) were erythromycin resistant. By the disk diffusion method (31) 4,917 (94.7%) showed the MLSB phenotype and 277 (5.3%) showed the M phenotype (134 isolates were from blood, 55 were from the lower respiratory tract, 20 were from patients with otitis, 21 were from patients with conjunctivitis, and 47 were from miscellaneous sources). Table 1 shows the evolution of rates of erythromycin resistance and the phenotypes. Although the MLSB phenotype is dominant among erythromycin-resistant pneumococci, our study shows that the proportions of isolates with the M phenotype increased significantly from 3.3% in 1998 to 8.9% in 2003 (P < 0.01) (Table 1). Similar rates of the M phenotype were found among erythromycin-resistant isolates from children (age, <15 years) and adults (4.6% and 5.1%, respectively).

TABLE 1.

Evolution of resistance, phenotypes, and related serotypes of erythromycin-resistant pneumococci

Yr Total no. of isolates Overall rate (%)
No. of Eryr isolates % Isolates of the following phenotype
Eryra Phenotype
M
MLSB
MLSB Mb Totalb Serotype14b
1998 1,844 35.7 34.5 1.2 658 3.3 1.2 96.7
1999 2,664 34.5 33.3 1.2 919 3.5 1.5 96.5
2000 2,676 34.8 33.6 1.2 931 3.3 1.9 96.7
2001 2,546 35.5 33.6 1.9 904 5.4 3.7 94.6
2002 2,831 36.2 33.5 2.7 1,025 7.4 4.8 92.6
2003 2,523 30.0 27.3 2.7 757 8.9 5.8 91.1
Total 15,084 34.4 32.6 1.8 5,194 5.3 3.2 94.7
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a

Eryr, erythromycin resistant.

b

Statistically significant (P < 0.05) increase in the rates from 1998 to 2003.

Resistance genes.

Classically, two mef genes have been identified in pneumococci, mef(A) and mef(E), and these are carried by different genetic elements (6). The mef(A) gene, which is usually found in serotype 14 strains of the England14-9 clone, is carried by a defective transposon (Tn1207.1), whereas the mef(E) gene, which has been identified in different serotypes and clones, is located in the MEGA element (2, 6-9, 21, 24, 34). Recently, a new mef gene, mef(I), has been described in two serotype 11A strains (sequence type 1774 [ST1774]) (4).

The mef gene was detected by PCR (32) in all 277 M-phenotype pneumococci studied. After digestion with BamHI (24), 242 (87.4%) isolates had the mef(E) gene [this approach could not differentiate between mef(E) and mef(I)] and 35 (12.6%) had the mef(A) gene.

Consistent with the findings of previous studies (1, 17), we found that the erythromycin MICs of mef(A)-carrying pneumococci were higher (range, 8 to 128 μg/ml; geometric mean, 29.0 μg/ml) than those of mef(E)-carrying strains (range, 2 to 128 μg/ml; geometric mean, 12.9 μg/ml). These findings could be due to structural differences in the protein or at the site of codifying genes (1).

Only 30 (12.4%) of 242 mef(E)-carrying isolates were tetracycline resistant [positive for tet(M) and int genes by PCR (1, 7)] and had unrelated pulsed-field gel electrophoresis (PFGE) patterns. The association of the mef(E) and the tet(M) genes was reported previously (1, 25, 30), and the genetic element harboring both genes, Tn2009, was recently described (7).

Serotypes and genotypes related to mef genes.

Serotyping and PFGE (SmaI) were performed with all mef-carrying isolates, as described previously (14, 22, 33). Twelve strains with the dominant PFGE patterns were selected for multilocus sequence typing (MLST) (12).

Nineteen different serotypes were found among 242 mef(E)-carrying isolates, with the most frequent being serotype 14 (55.8%), nontypeable (10.3%), and serotype 11A (7.9%). Ninety-two PFGE patterns were observed among the mef(E)-carrying strains, with the Spain9V-3 clone (55.8%) and genotype 11A-ST62 (7.0%) being the major clones found (Table 2). Thirty-one (88.6%) of 35 mef(A)-carrying isolates were serotype 14 and belonged to the England14-9 clone (Tables 2 and 3).

TABLE 2.

Evolution of pneumococcal genotypes related to the mef(A) or mef(E) gene

Yr No. (%) of isolates of the indicated genotypes harboring:
mef(E)
mef(A)
Total Spain9V-3 11A-ST62 Other genotypes Total England14-9 Other genotypes
1998 20 5 (25.0) 1 (5.0) 14 (70.0) 2 2 0
1999 25 10 (40.0) 3 (12.0) 12 (48.0) 7 6 1
2000 28 16 (57.1) 1 (3.6) 11 (39.3) 3 2 1
2001 45 29 (64.4) 0 16 (35.6) 4 4 0
2002 66 41 (62.1) 8 (12.1) 17 (25.8) 10 9 1
2003 58 34 (58.6) 4 (6.9) 20 (34.5) 9 8 1
Total 242 135 (55.8) 17 (7.0) 90 (37.2) 35 31 (88.6.6) 4 (11.4)
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TABLE 3.

Characteristics of strains selected for MLST

Strain RPa Serotype Genotype Source mef gene Allele
ST
aroE gdh gki recP spi xpt ddl
67/02 PESxT 14 Spain9V-3 Conjunctivitis E 7 11 10 1 6 8 1 156
544/02 PESxT 14 Spain9V-3 Blood E 7 5 10 1 6 8 1 144b
673/02 PESxT 14 Spain9V-3 Blood E 7 11 10 1 6 8 1 156
1615/02 PESxT 14 Spain9V-3 Sputum E 7 11 10 1 6 8 1 156
25/99 PESxT 14 Spain9V-3 Blood E 7 11 10 1 6 8 1 156
485/00 PESxT 14 Spain9V-3 Sputum E 7 11 10 1 6 8 1 156
1529/98 ESxT 11A 11A-ST62 Pus E 2 5 29 12 16 3 14 62
2472/02 ESxT 11A 11A-ST62 Blood E 2 5 29 12 16 3 14 62
413/02 E 14 England14-9 Blood A 1 5 4 5 5 1 8 9
1738/02 E 14 England14-9 CSFc A 1 5 4 5 5 1 8 9
2184/01 E 14 England14-9 CSF A 1 5 4 5 5 1 8 9
3208/02 E 14 England14-9 Blood A 1 5 4 5 5 1 5 9
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a

RP, resistance pattern; P, penicillin nonsusceptible (MIC ≥ 0.12μg/ml); E, erythromycin nonsusceptible (MIC ≥ 1 μg/ml); SxT, co-trimoxazole nonsusceptible (MIC ≥ 1/19 μg/ml).

b

Single-locus variant of ST156.

c

CSF, cerebrospinal fluid.

Five of 26 international clones described by the Pneumococcal Molecular Epidemiology Network (22) were resistant to macrolides, with the resistance encoded by mef genes. Two of them, England14-9 and Taiwan19F-14 (13, 21), are the major contributors to the worldwide dissemination of M-phenotype strains (http://www.mlst.net). In contrast, our results show that the majority (48.7%, 135/277) of the M-phenotype pneumococci isolated in Spain belonged to the Spain9V-3 clone and harbored the mef(E) gene, whereas only 11.2% (35/277) of the strains belonged to the England14-9 clone and harbored the mef(A) gene (Table 2). No Taiwan19F-14 clone was observed among the 16 serogroup 19 isolates studied.

The Spain9V-3 clone was first identified in 1987 in Spain and France and is now one of the most important invasive pneumococci worldwide (www.mlst.net) (5). Strains of this clone are usually resistant to penicillin and co-trimoxazole; however, since 1998 some strains of this clone have acquired the mef(E) gene (20). In the United States, only 37 (14.1%) of mef(E)-carrying strains were related to the Spain9V-3 clone (21), and all but one were of serotype 9V. In contrast, we found that 96.3% of the mef(E)-carrying pneumococci of the Spain9V-3 clone were serotype 14, demonstrating a phenomenon of capsular switching between serotypes 9V and 14.

The England14-9 clone harboring mef(A) has been described as predominant among M-phenotype pneumococci isolated in England, Italy, and Greece (1, 6, 15, 24). In our study this clone ranked second. In contrast, the strains of the England14-9 clone described in the United States carried the mef(E) gene (21).

Strains of serotype 11A with ST62 have previously been found in Spain among erythromycin-susceptible pneumococci causing meningitis (11). Our results show that isolates of genotype 11A-ST62, which harbor the mef(E) gene, rank third among the M-phenotype pneumococci isolated in Spain. Strains of serotype 11A harboring the mef(A) gene have been sporadically described in Italy (23), and strains of serotype 11A harboring the mef(E) gene have been described in Hungary (9) and Canada (34).

In common with other findings (34), our results show that a third of the mef(E) isolates had unrelated genotypes, thus suggesting the horizontal spread of this gene. We previously reported a high prevalence of macrolide resistance mediated by the mef(E) gene in viridans group streptococci (2), which may act as a reservoir of the mef(E) gene and contribute to the horizontal transmission of macrolide resistance in pneumococci, as is the case in other resistance genes (3).

In conclusion, although the mef(E) gene may spread horizontally, the clonal dissemination of the serotype 14 variant of the Spain9V-3 clone harboring the mef(E) gene is a major contributor to the emergence of M-phenotype pneumococci in Spain.

Acknowledgments

This work was supported by the Spanish Pneumococcal Infection Study Network G03/103 (Red Temática de Cooperación del Fondo de Investigaciones Sanitarias de la Seguridad Social). We are grateful for permission to use the pneumococcal MLST database at Imperial College London, funded by the Wellcome Trust.

We thank Elena Pérez for her excellent technical support.

The general coordinator of the Spanish Pneumococcal Infection Study Network (G03/103) is Román Pallarés. The participants and centers include Ernesto García (Centro de Investigaciones Biológicas, Madrid); Julio Casal, Asunción Fenoll, and Adela G. de la Campa (Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid); Emilio Bouza (Hospital Gregorio Marañón, Madrid); Fernando Baquero (Hospital Ramón y Cajal, Madrid); Francisco Soriano and José Prieto (Fundación Jiménez Díaz and Facultad de Medicina de la Universidad Complutense, Madrid); Román Pallarés and Josefina Liñares (Hospital Universitari de Bellvitge, Barcelona); Javier Garau and Javier Martínez Lacasa (Hospital Mutua de Terrassa, Barcelona); Cristina Latorre (Hospital Sant Joan de Déu, Barcelona); Emilio Pérez-Trallero (Hospital Donostia, San Sebastián); Juan García de Lomas (Hospital Clínico, Valencia); and Ana Fleites (Hospital Central de Asturias).

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